Palbociclib

Common name: Palbociclib; PD-0332991; PD0332991; PD 0332991; Ibrance
Trademarks: Ibrance
Molecular Formula: C24H29N7O2
CAS Registry Number: 571190-30-2

CAS Name: 6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino} pyrido[2,3-d]pyrimidin-7(8H)-one

Molecular Weight: 447.532
SMILES:CC1=C(C(=O)N(C2=NC(=NC=C12)NC3=NC=C(C=C3)N4CCNCC4)C5CCCC5)C(=O)C
InChI Key: AHJRHEGDXFFMBM-UHFFFAOYSA-N
InChI:InChI=1S/C24H29N7O2/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)
Activity: Breast Cancer Drug; Cancer Drug; CDK4 Inhibitor; CDK6 Inhibitor; Dual Kinase Inhibitor; Protein Kinase Inhibitor; Cyclin Dependent Kinase Inhibitor; Treatment of Metastatic Breast Cancer
Status: Launched 2015
Originator: Pfizer


Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. In vitro palbociclib reduced cellular proliferation of ER-positive breast cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle [1].

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors [2].

On February 3, 2015, the U. S. Food and Drug Administration granted accelerated approval to palbociclib (IBRANCE, Pfizer) for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

The approval of palbociclib is based on a randomized, multicenter, open-label trial in postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) breast cancer who had not received previous systemic treatment for advanced disease. The trial enrolled 165 patients randomly allocated to receive either palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg daily continuously throughout the 28-day cycle) or letrozole alone.

Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Forty- nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease; 48% had visceral disease, 75% had bone disease and 19% had bone only disease.

The major efficacy outcome measure was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST). Median investigator-assessed PFS was 20.2 months (95% CI 13.8, 27.5) in the palbociclib plus letrozole arm and 10.2 months (95% CI 5.7, 12.6) in the letrozole alone arm [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)]. The treatment effect of the combination on PFS was also supported by a retrospective radiographic independent review [HR 0.621 (95% CI: 0.378, 1.019).]  Overall response rate in patients with measurable disease (investigator assessment) was higher in the palbociclib plus letrozole compared to the letrozole alone arm (55.4% versus 39.4%).

Most common adverse reactions (greater than or equal to 10%) were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving palbociclib plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%).

The recommended dose and schedule of palbociclib is 125 mg daily for 21 consecutive days followed by 7 days off treatment with letrozole 2.5 mg daily continuously throughout the 28-day cycle [1].

References:
1. Cadoo, K. A.; et. al. Palbociclib: an evidence-based review of its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press) 2014, 6, 123-133. (activity)
2. Fry, D. W.; et. al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004, 3(11), 1427-1438.